Listeriosis is an important food borne disease that causes approximately 2,500 cases of serious illness and as many as 500 deaths per year in the United States. Resistance to listedosis requires both innate and adaptive immune responses, with the former being dependent on release of the inflammatory cytokine TNF-alpha and the rapid mobilization of granulocytes and mononuclear phagocytes to sites of infection. The aryl hydrocarbon receptor (AhR) is a highly conserved member of the basic loop helix-PAS protein family. In vertebrates, it regulates a powerful signaling system when it is activated by environmental toxicants such as polychlorinated hydrocarbons (e.g. dioxin) and polycyclic aromatic hydrocarbons (e.g. benzo[a]pyrene). In invertebrates the AhR is involved in environmental sensing, regulation of biological clocks and normal development, and it retains some of these functions within vertebrates. Activation of the AhR can have a deleterious effect on various aspects of the immune system, including host defense against subsequent microbial infection. However, AhR activation also leads to release of TNF-alpha that is responsible for some of its biological effects. We have obtained exciting and provocative preliminary data indicating that AhR null mice are less resistant to experimental listeriosis than their wild type counterparts. The overall goal of this project is to understand how the AhR influences resistance to L. monocytogenes infection. The central hypothesis is that the AhR is required for optimal development and expression of innate immunity against a primary L. monocytogenes infection, and that this involves AhR dependent release of TNF-alpha. The specific aims of the proposal are as follows: 1) Define the requirement of the AhR for resistance to listeriosis in mice; 2) Determine whether the AhR influences the survival and multiplication of L. monocytogenes in hepatocytes; and 3) Investigate the effects of the AhR on the anti-listerial activity of granulocytes and macrophages. The role of TNF-alpha in the responses observed in all 3 aims will be determined. At the completion of this study, we will have novel and important new insights into the participation of the AhR in innate immunity against L. monocytogenes infection. These studies may identify potential new targets for enhancing innate immunity against listeriosis, perhaps by administration of AhR agonists (flavenoids, etc.), that signal through the AhR without triggering the adverse events that follow binding of environmental toxicants.